The analysis of formulated drug products has been of increasing importance over the last several years. The potential for decomposition of the active pharmaceutical ingredient (API) has always placed emphasis on the analysis of the compound itself. This has routinely been accomplished by techniques such as HPLC. However, HPLC is powerless to speak to the crystal form of the API. For crystal form analysis, scientists have placed emphasis on techniques such as XRPD, infrared and Raman spectroscopy, and solid-state NMR. For the characterization of the API, these ‘fingerprint’ techniques are excellent individually, and even more powerful in combination. However, the API is often a minor component by weight in a tablet or other formulation. The presence of the excipients can interfere with the analysis of crystal forms.
In the evaluation of crystal form, for best results one must separate the excipients from the API in a pharmaceutical formulation. Dissolution is not an option, since the crystal form is lost in solution. The API has frequently been formulated as a salt if the molecule itself is not readily water-soluble. Most excipients are also water-soluble.
The crystallography of five decades past was not based on a high production of single crystal X-ray structures. Indeed, by the early 1970's a rule of thumb was that a crystallographer with a modern (as of 1970) four-circle X-ray diffractometer and a moderate size research group should strive to do five or six structures per year. Times have changed. Today, moderate sized research groups commonly do more than ten X-ray crystal structures per week. Computer and diffractometer power have consumed much of the art of the crystallography of the 1960's.
In the 1960's and 1970's, the measurement of the density of single crystals was, depending on the journal, mandatory for publication. The density measurement was performed by placing the crystal in a fluid medium in which the crystal was not soluble. The density of the fluid was then adjusted (by adding solute or other miscible fluids) so that the crystal under analysis would float half way up in the column of fluid. At that point, the density of the crystal was equal to the density of the fluid medium.
Therefore, there is a need to provide a new and improved method for physically separating an API from excipients in a pharmaceutical formulation.